By Shawn M. Schmitt
Communications Specialist, Enzyme
The widespread collection and use of real-world data (RWD) by pharmaceutical and MedTech manufacturers to support new product submissions is teetering on a tipping point in these industries, yet one expert and longtime RWD proponent says many companies are still gun-shy about presenting such data to a regulator’s review teams despite a strong desire to get novel drugs, medical devices, and diagnostics to market faster.
“The biggest single problem I see is that there’s still some resistance at the rank-and-file level at these companies to using real-world evidence [RWE] in regulatory applications. They can sing the song all they want, but they really have to be prepared to fight to convince a review team that what they’re doing and the RWD they’re using is appropriate. That’s certainly the biggest single gap that I’ve seen from the manufacturing side when it comes to using this data,” said Stephen Weber, a consultant for Virginia-based NDA Partners and a former Medical Officer for the US Food and Drug Administration (FDA).
Incorporating RWD into regulatory submission workflows is nevertheless a hurdle that manufacturers must increasingly jump if they want to ensure a successful product launch. After all, cobbling together a prospective randomized study for drugs, devices, and in vitro diagnostics (IVDs) nowadays can consume too much of a company’s time and money. While such studies are arguably the best way to prove to regulators that products are indeed safe and effective, they can also be a risky proposition for firms, making the use of RWD and RWE a viable, sensible substitute.
“I think there’s still a place for prospective randomized trials, but it’s so expensive and so difficult and so time-consuming to collect that data that companies are certainly going to be more interested in real-world evidence as time goes on, because they’re either going to have to use that or they just won’t bring their product to market. Really, there are no other good options these days,” Weber said, adding that it has “become almost toxic” for pharmaceutical and MedTech makers to conduct prospective randomized studies.
“If a company is lucky, all of the data will come in from a prospective randomized trial in, say, five years. But that’s a huge problem when manufacturers have investors champing at the bit to get products to patients,” Weber said. “But if a company can get line-item data for its device or IVD and make a control group using real-world data, then all of a sudden, they can be in a market three years earlier – that’s enormous and it’s cheaper.
“You just can’t do a $10M clinical trial that fails, because then you’re done. Your company’s done. And you’re probably done. People just can’t take that kind of risk anymore,” he added. “Randomized trials have become more and more complicated and more expensive and more difficult to execute to the point that it is pretty obvious that it can strangle innovation.”
Still, Weber recognizes that it can sometimes be a “hard sell” for manufacturers to make the case to regulators that RWD and RWE can be used in lieu of a costly, time-sucking trial.
“Companies have to approach review teams and make a strong case for real-world evidence because – even now – the first thing the FDA will likely say is that they would rather see a prospective randomized study,” Weber said. “I think that’s going to change more and more, but that’s probably the biggest problem right now. But the guidance documents from the FDA on this topic have been pretty solid, so if manufacturers follow those guidances, they ought to be able to make it work.”
The FDA has published a handful of guidance docs since 2017 that address the use of RWE in regulatory decision-making. While he recommends that manufacturers familiarize themselves with all applicable guidances, Weber strongly urges companies to read the agency’s comprehensive 37-page document released in 2018 that lays bare the framework for its RWE program.
The EU’s Approach to RWE
Outside the US, regulators are “playing catch-up” when it comes to using real-world evidence in deciding which products reach market, Weber said. He noted, however, that there are EU-based groups that are strongly pushing for better use of RWE, including IDERHA – Integration of Heterogeneous Data and Evidence towards Regulatory and HTA Acceptance – and the Data Analysis and Real World Interrogation Network, or DARWIN EU.
“The EU doesn’t have RWE quite nailed down as well as regulators do in the US, but they’re working on it,” he said. “One of the biggest challenges facing the EU in regard to RWE is that every country in Europe is different, and some countries and their associated regulatory bodies have been pretty real-world evidence friendly, and others have not. So in addition to trying to figure out what is best to do, a manufacturer also has to figure out what’s going to work in every country and determine which competent authorities will accept real-world evidence. While RWE could be used in, say, Holland, a company may get completely turned down in Denmark with the same data.
“So that’s the problem that I see in Europe,” he noted. “It is difficult to get everybody there to agree on a lot of things, and this is certainly one of them. I think the most important initiative that has helped is DARWIN EU.”
Further, manufacturers in the EU, particularly those that make medical devices, are relying on product registries when compiling RWE. Such registries gather real-world data related to the safety and effectiveness of products.
“Most of the orthopedic devices that I review in my capacity as a consultant use real-world evidence gathered post-market. Registries are huge for post-market, and certainly when companies are writing CERs in Europe, they’re involving publications and registry data,” Weber said.
Part of a product’s Technical File, a CER – or Clinical Evaluation Report – is mandatory for all devices as they go through the CE Marking and conformity assessment process prior to reaching market.
“It’s pretty uncommon in my experience to have a CER where the manufacturer has set up a brand-new prospective randomized study. It’s just not really how it’s being done anymore,” Weber said. “So I think the use of registries is going to become even more common as companies become more comfortable with RWE. And registries are only getting better by including even more great, detailed information. That’s powerful.”
He went on: “Europe is indeed catching up slowly. Again, the biggest problem with Europe is what flies in Denmark might not fly in Holland. It’s difficult and time consuming, but that said, they’ve made the effort to do it. They’ve put in a lot of money and time. After all, nobody wants to be the country where companies can’t develop medical devices because you don’t have the infrastructure. So absolutely I think that’s going to come around.”
